Faculty Bibliography

BACKGROUND:Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS:or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS:A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (0.95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS:supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion

OBJECTIVE: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. The aim of this study was to identify factors associated with patients' recognition of SLE as an independent risk factor for CVD and their perception of their personal CVD risk. METHODS: SLE patients were sent questionnaires that assessed demographic characteristics, any CVD risk factors, and information regarding the CVD counseling they had received from their physicians. Variables significantly associated with the outcomes were analyzed using logistic regression models. RESULTS: Information obtained from 226 questionnaires was analyzed. Fifty-eight percent of the respondents reported receiving no CVD counseling from a physician. Patients who recalled receiving counseling from a physician were 2.3 times more likely (P = 0.02) to recognize SLE as a CVD risk factor and 3.2 times more likely (P = 0.02) to perceive themselves as being at risk of CVD compared with those patients who did not receive physician counseling. Receiving physician CVD counseling was the strongest predictor of a patient's self-perception of CVD risk. Those patients at intermediate to high risk (n = 167) who reported having received counseling were 5.3 times as likely (P = 0.007) to perceive themselves to be at higher risk of CVD compared with similar patients who did not receive counseling. Younger patients were 4.2 times as likely (P = 0.002) as older patients to recognize SLE as a CVD risk factor. Other variables associated with patients' self-perceptions of CVD risk included family history of CVD and hypertension. CONCLUSION: Physician counseling regarding CVD in SLE patients has an important impact on patients' awareness of SLE as a CVD risk factor and their self-perception of CVD risk.

AIMS/HYPOTHESIS: Partial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin. METHODS: A 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy. RESULTS: Eighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l). CONCLUSION: r-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.

CONTEXT: Acquired generalized lipodystrophy (AGL) is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes (T1D) coexist. OBJECTIVE: Our objective was to describe the response to leptin therapy in patients with coexisting AGL and T1D and to document the autoimmune diseases associated with AGL. DESIGN AND SETTING: We conducted an open-label prospective study at the Clinical Research Center of the National Institutes of Health. PATIENTS: Participants included 50 patients with generalized or partial lipodystrophy (acquired or congenital); two patients had both AGL and T1D. INTERVENTION: Patients were treated with 12 months of recombinant human leptin administration to achieve high-normal serum concentrations. RESULTS: Two patients had both AGL and T1D. The first was diagnosed with T1D at age 8 yr. Beginning at age 11 yr, he developed generalized lipodystrophy, elevated transaminases, and poor glycemic control [hemoglobin A 1c (HbA 1c) 10.7%] despite markedly increased insulin requirements (3.3-5 U/kg.d). Further evaluation revealed hypoleptinemia and hypertriglyceridemia. At age 15 yr, leptin therapy was initiated, and after 1 yr, his insulin requirements fell to 1 U/kg.d, his glycemic control improved (HbA 1c 8.4%), and both his triglycerides and transaminases normalized. The second patient developed concurrent AGL and T1D at age 6 yr. Despite insulin doses of up to 32 U/kg.d, she developed poor glycemic control (HbA 1c 10.6%), hypertriglyceridemia (2984 mg/dl), elevated transaminases, and nonalcoholic steatohepatitis. At age 13 yr, leptin therapy was started, and after 1 yr, her glycemic control improved (HbA 1c 7.3%) and her insulin requirements decreased (17 U/kg.d). Her triglycerides remained elevated but were improved (441 mg/dl). CONCLUSIONS: Long-term recombinant leptin therapy is effective in treating the insulin resistance of patients with the unusual combination of T1D and AGL.

After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid's putative role as a 'danger signal' in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon

OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA

The Dunnigan-type familial partial lipodystrophy (FPLD) is characterized by a variable loss of fat from the extremities and trunk and excess subcutaneous fat in the chin and supraclavicular area. Associated metabolic abnormalities include hypoleptinemia, insulin resistance, and dyslipidemia. Our goal was to observe changes in metabolic parameters for patients with FPLD on long-term leptin replacement and to compare the metabolic characteristics seen in FPLD with those seen in generalized lipodystrophy (GL) from our previous studies. This was an open-label study of 6 patients with FPLD receiving maximal doses of oral antidiabetic and lipid-lowering medications at baseline. Recombinant leptin was given through twice-daily subcutaneous injections at a maximal dose of 0.08 mg/kg per day over 12 months to simulate normal to high normal physiologic levels. Triglycerides were reduced by 65% at 4 months (749+/-331 to 260+/-58 mg/dL) and significantly reduced at 12 months for 5 patients (433+/-125 to 247+/-69 mg/dL; P=.03). Total cholesterol also decreased (280+/-49 to 231+/-41 mg/dL; P=.01). Insulin sensitivity and fasting glucose levels (190+/-26 to 151+/-15 mg/dL; P<.01) improved. Glucose tolerance and glycosylated hemoglobin levels (8.4%+/-0.6% to 8.0%+/-0.4%; P=.07) did not change. As shown in patients with GL, patients with FPLD have improvement in triglycerides, fasting glucose, and insulin sensitivity with leptin replacement. In contrast to the patients with GL, the patients with FPLD are older, have higher leptin levels, and notably lower insulin secretion for a similar degree of hyperglycemia. Low-dose recombinant methionyl human leptin for patients with FPLD has an important role in improving triglycerides, beyond that of available lipid-lowering agents. In improving glycemic control, normalization of glucose tolerance in hypoinsulinemic patients with FPLD requires insulin and leptin therapy. This is the first study to examine the effects of long-term leptin replacement in patients with FPLD.

Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed